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. Author manuscript; available in PMC: 2021 May 1.
Published in final edited form as: Curr Opin Cardiol. 2020 May;35(3):199–206. doi: 10.1097/HCO.0000000000000725

Functional Characterization of Long Non-Coding RNAs

Joseph B Moore IV 1,2, Shizuka Uchida 1,2,3
PMCID: PMC7236552  NIHMSID: NIHMS1585040  PMID: 32068613

Abstract

Purpose of review

Mounting evidence suggests that long non-coding RNAs (lncRNAs) are essential regulators of gene expression. While few lncRNAs have been the subject of detailed molecular and functional characterization, it is believed that lncRNAs play an important role in tissue homeostasis and development. In fact, gene expression profiling studies reveal lncRNAs are developmentally regulated in a tissue- and cell-type specific manner. Such findings have brought significant attention to their potential contribution to disease etiology. The current review summarizes recent studies of lncRNAs in the heart.

Recent findings

lncRNA discovery has largely been driven by the implementation of next generation sequencing technologies. To date, such technologies have contributed to the identification of tens of thousands of distinct lncRNAs in humans—accounting for a large majority of all RNA sequences transcribed across the human genome. While the functions of these lncRNAs remain largely unknown, gain- and loss-of-function studies (in vivo and in vitro) have uncovered a number of mechanisms by which lncRNAs regulate gene expression and protein function. Such mechanisms have been stratified according to three major functional categories: 1) RNA sponges (RNA-mediated sequestration of free miRNAs; e.g., H19, MEG3, and MALAT1); 2) transcription-modulating lncRNAs (RNA influences regulatory factor recruitment by binding to histone modifiers or transcription factors; e.g., CAIF, MANTIS, and NEAT1); and 3) translation-modulating lncRNAs (RNA modifies protein function via directly interacting with a protein itself or binding partners; e.g., Airn, CCRR, and ZFAS1).

Summary

Recent studies strongly suggest that lncRNAs function via binding to macromolecules (e.g., genomic DNA, miRNAs, or proteins). Thus, lncRNAs comprise an additional mode by which cells regulate gene expression.

Keywords: long non-coding RNAs, microRNAs, cardiovascular disease

Introduction

Long non-coding RNAs (lncRNAs) by definition are any non-protein-coding transcripts whose lengths are longer than 200 nucleotides. To date, the identification of most of these lncRNAs are based on the computational characterization of RNA sequencing (RNA-seq) results, which is rather error prone as second-generation sequencing approaches (also known as next generation sequencing) can only produce short reads (up to 400 bp). Thus, the complete transcript of lncRNA cannot be read by this technology. To overcome this limitation, third-generation sequencing is being employed to capture the full length (up to 15 kb) of transcripts. However, the read depth of this new technology is still a challenge. As many lncRNAs are expressed in a cell-type specific manner, further development of third-generation sequencing technology is needed to allow reading of lncRNAs from a single cell. In addition to the identification of lncRNAs, an outstanding issue with lncRNA research is that most lncRNAs are species-specific; in other words, many are not conserved across species (1). Although the basis of lncRNA diversity is not necessarily clear, such an observation may be associated with the progression of complexity in biological evolution. Nevertheless, it has been noted that organismal complexity directly correlates with the number of genome encoded lncRNAs; whereas more complex species possess a greater number of genome-encoded lncRNAs than that of lower order species, yet, the number of protein-coding genes remain quite comparable (e.g., worms and humans) (2). This trend must be interpreted carefully, as the number of lncRNAs are solely based on how well a genome of each organism is characterized (3). Thus, rather than sequence conservation of lncRNAs, most researchers use expression similarity and positional conservation (e.g., locus conservation of lncRNAs among species) to identify species-conserved lncRNAs (4–7).

The broad definition of lncRNAs may include newly identified RNA transcripts that do not fall under the category of protein-coding genes—such as those deriving from the transcription of pseudogenes, whose genomic DNA sequences are similar to normal protein-coding genes but do not encode a functional protein (8–11). Further, this definition also applies to circular RNAs (circRNAs) generated from mRNA backsplicing, wherein a downstream splice donor site is covalently joined to an upstream splice acceptor site (12–14). Recently, the fundamental definition of lncRNAs as non-protein-coding has been challenged by the discoveries and characterizations of micropeptides, which encode for small peptides from the short open reading frames of lncRNAs (15–19). Although pseudogene, circRNA, and micropeptide function are of sustained interest to the scientific community at large (20–22), the current review will focus on recent lncRNAs that have been the subject of extensive functional characterization within the cardiovascular field.

As the interest to understand the functions of lncRNAs has increased tremendously in recent years, the cardiology field has witnessed a surge of studies relating to lncRNAs and their role in cardiovascular biology and disease etiology. Since 2018, there has been over 80 published studies aiming to uncover the fundamental biological functions of lncRNAs in the heart (PubMed accessed on 09/08/2019) (Figure 1). A majority of these studies have relied on gain- and/or loss-of-function experiments in immortalized (e.g., mouse HL-1, rat H9c2 cells) or primary rodent-derived cardiomyocytes to interrogate the physiological significance of various target lncRNAs on cardiomyocyte biology and function (e.g., apoptosis, migration, and/or hypertrophy). The molecular underpinnings of these phenomena have been attributed to defined lncRNA mechanisms that fall into three major functional categories—namely, RNA sponges, transcription-modulating lncRNAs, and translation-modulating lncRNAs. Said functions will be briefly reviewed below.

Figure 1. Recently characterized lncRNAs and their binding partners in the cardiovascular system.

Figure 1.

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The lncRNAs are shown in bold and italic.

Many lncRNAs bind to miRNAs: a generalized mechanism?

(23–26)Early investigations interrogating potential lncRNA mechanisms suggest that lncRNAs may act as scaffolds for epigenetic factors, such as Polycomb Repressive Complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2); however, later studies reveal that these epigenetic factors promiscuously interact with many RNA species, not only lncRNAs (23–27)—casting doubt that lncRNA-mediated recruitment of co-activator/co-repressor complexes is a chief mechanism of action. As a result of these and other studies, the interest to investigate the function of lncRNAs as epigenetic modifiers quickly faded away in recent years. Since the discovery of miRNA (28), numerous studies have been conducted to discover, characterize, and elucidate their functions in various research fields around the world—which has fueled the development of new experimental techniques (e.g., antagomir, miRNA mimics) and identification of cognate miRNA targets [i.e., 3’-untranslated regions (UTR)]. This course of investigation inevitably expanded to include the investigation of lncRNAs as potential miRNA sponges [also referred to as, competing endogenous RNAs (ceRNAs)], which can be viewed as an additional layer of post-transcriptional control of gene expression. Intriguingly, the longer a lncRNA is, the more likely it is to contain binding sites for miRNAs, as the core seed sequences are very short [6 ~ 8-mers (29)]. We also report that many lncRNAs can be detected from cross-linking immunoprecipitation followed by next generation sequencing (CLIP-seq) data, which aim to identify the potential targets of RNA-induced silencing complex (RISC) by using anti-argonaute (AGO) antibodies (30). Thus, many lncRNAs function as miRNA sponges, which are evident from the recent studies summarized in Table 1.

Table 1.

List of recently identified lncRNAs functioning as miRNA sponges in the heart.

lncRNA Cell/Tissue Type Function/Mechanism Reference
AK088388 Cardiomyocytes (HL-1 cells) Sponges miR-30a, which targets Beclin-1 and LC3-phosphatidylethanolamine conjugate (LC3-II) to regulate autophagy (45)
Cardiac hypertrophy related factor (CHRF) Neonatal mouse cardiomyocytes Sponges miR-93, which targets AKT serine/threonine kinase 3 (Akt3) to induce cardiac hypertrophy (46)
Cardiac hypertrophy-associated regulator (CHAR) Mice and neonatal rat ventricular cells Sponges a pro-hypertrophic miRNA, miR-20b, which represses phosphatase and tensin homolog (PTEN) expression and indirectly increases AKT activity (47)
Cardiac regeneration-related lncRNA (CAREL) Transgenic mice, human induced pluripotent stem cell-derived cardiomyocytes Sponges miR-296, which targets tumor protein p53-inducible nuclear protein 1 (Trp53inp1) and integral membrane protein 2A (Itm2a) to regulate cardiomyocyte proliferation and heart regeneration in postnatal and adult heart after injury (48)
Ccancer susceptibility 15 (CASC15) Neonatal mouse cardiomyocytes Sponges miR-432–5p, which targets Toll-like receptor 4 (TLR4) to facilitate cardiac hypertrophy (49)
Five prime to Xist (FTX) Neonatal mouse cardiomyocytes Sponges miR-29b-1–5p, which targets Bcl-2-like protein 2 (Bcl2l2) to regulate cardiomyocyte apoptosis (50)
GATA1 activated lncRNA (Galont) Neonatal mouse cardiomyocytes Sponges miR-338, which targets autophagy related 5 (ATG5) to promote autophagic cell death (51)
Growth arrest-specific transcript 5 (GAS5) Cardiomyocytes (H9c2 cells) Sponges miR-142–5p, which targets tumor protein p53-inducible nuclear protein 1 (TP53INP1) to control PI3K/AKT and MEK/ERK signaling pathways (52)
H19 Cardiomyocytes (H9c2 cells) Sponges miR-29b-3p, which targets cellular inhibitor of apoptosis protein-1 (cIAP1). (53)
H19 Cardiac progenitor cells (CPCs) Sponges miR-200a-3p, which targets Sirt1 to regulate the proliferation and migration of CPCs (54)
H19 Cardiomyocytes (HL-1 cells) Sponges miR-874, which targets aquaporin 1 (AQP1) to control secretion of anti-inflammatory cytokines (55)
HOX transcript antisense RNA (HOTAIR) Cardiomyocytes (H9c2 cells) Sponges miR-519d-3p (56)
HOX transcript antisense RNA (HOTAIR) Cardiomyocytes (H9c2 cells) Sponges miR-125, which targets matrix metalloproteinase-2 (MMP2) to regulate cardiomyocytes proliferation and apoptosis (57)
Hypoxia-inducible factor 1α-antisense RNA 1 (HIF1A-AS1) Myocardial tissues Sponges miR-204, which targets suppressor of cytokine signaling 2 (SOCS2) (58)
KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) Neonatal mouse cardiomyocytes Sponges miR-384, which targets calcium voltage-gated channel subunit alpha1 C (CACNA1C) (59)
LINC00339 Neonatal rat cardiomyocytes, H9c2 cells Sponges miR-484 (60)
lnc-3215 Chicken embryos Sponges miR-1594, which regulates the troponin T type 2 (cardiac; TNNT2) expression (61)
lncRNA Plscr4 Neonatal mouse cardiomyocytes Sponges miR-214, which targets mitofusin-2 (Mfn2) to control cardiac hypertrophy (62)
LncRNA urothelial cancer associated 1 (lncUCA1) Neonatal rat cardiomyocytes Sponges miR-143, which targets mouse double minute 2 (MDM2) to regulate p53 signaling pathway (63)
LncRNA urothelial cancer associated 1 (lncUCA1) Neonatal mouse cardiomyocytes Sponges miR-184, which targets homeobox protein Hox-A9 (HOXA9) to regulate cardiac hypertrophy (64)
Maaternally expressed 3 (MEG3) Neonatal mouse cardiac fibroblasts Sponges miR-361–5p, which targets histone deacetylase 9 (HDAC9) to control cardiac hypertrophy (65)
MAGI1 intronic transcript 1 (MAGI1‐IT1) Cardiomyocytes (H9c2 cells) Sponges miR-302e, which targets dickkopf WNT signaling pathway inhibitor 1 (DKK1) to control Wnt/beta-catenin signaling (66)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Cardiomyocytes (H9c2 cells) Sponges miR-558, which targets Unc-51 like autophagy activating kinase 1 (ULK1) to decrease autophagy. (67)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Cardiomyocytes (H9c2 cells) Sponges miR-217, which targets sirtuin 1 (Sirt1) to regulate phosphatidylinositol 3-kinase/protein kinase 3 (PI3K/AKT) and Notch signaling pathways (68)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Knockout mice Sponges miR-503, which targets fibroblast growth factor 2 (FGF2) to regulate inflammatory cell number and functions (69)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Cardiomyocytes (AC16 cells) Sponges miR-200a-3p, which targets programmed cell death 4 (PDCD4) to regulate the proliferation, cell cycle progression and apoptosis of hypoxia-induced myocardial cells (70)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Endothelial progenitor cells Sponges miR-15b-5p, which targets mitogen-activated protein kinase 1 (MAPK1) to increase cell viability while repressing apoptosis via activating mTOR signaling pathway (71)
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Cardiac progenitor cells (CPCs) Sponges miR-125, which targets jumonji domain containing 6 (JMJD6) to modulate CPC proliferation and migration potential (72)
Myocardial infarction-associated transcript (MIAT) Neonatal rat cardiomyocytes Sponges miR-93, which targets Toll-like receptor 4 (TLR4) to contribute to cardiac hypertrophy (73)
n379519 Neonatal rat cardiac fibroblasts Sponges miR-30 to regulate myocardial collagen deposition (74)
Nuclear paraspeckle assembly transcript 1 (NEAT1) Cardiomyocytes Sponges miR-125a-5p, which targets B-cell lymphoma-2-like 12 (BCL2L12) to inhibit cardiomyocyte apoptosis (75)
Pro-cardiac fibrotic lncRNA (PCFL) Overexpressing and knockout mice Sponges miR-378, which targets growth factor receptor-bound protein 2 (GRB2) to suppress the production of collagens in cardiac fibroblasts. (44)
Pro-fibrotic lncRNA (PFL) Neonatal mouse cardiomyocytes and cardiac fibroblasts Sponges let-7d, which targets platelet-activating factor receptor (Ptafr) to promote cardiac fibrosis (76)
RNA component of mitochondrial RNA processing endoribonuclease (RMRP) Cardiomyocytes (H9c2 cells) Sponges miR-206, which targets autophagy related 3 (Atg3) to activate PI3K/AKT/mTOR pathway (77)
small nucleolar RNA host gene 1 (SNHG1) Human cardiomyocyte primary cells Sponges miR-195, which targets BCL-2 like protein 2 (BCL2L2) to attenuate cardiomyocyte apoptosis (78)
Taurine up- regulated 1 (TUG1) Neonatal mouse cardiomyocytes Sponges miR-142–3p, which targets high mobility group box 1 (HMGB1) and Ras-related C3 botulinum toxin substrate 1 (Rac1), to mediate cell apoptosis and autophagy. (79)
Taurine up- regulated 1 (TUG1) Vascular smooth muscle cells Sponges miR-21, which targets phosphatase and tensin homolog (PTEN) (80)
Taurine up- regulated 1 (TUG1) Adult mouse cardiac fibroblasts Sponges miR-29c (81)
Taurine up- regulated 1 (TUG1) Cardiomyocytes (H9c2 cells) Sponges miR-124, which targets hydrogen peroxide-inducible clone-5 (Hic-5) to inhibit hypoxia injury (82)
Taurine up- regulated 1 (TUG1) Valve interstitial cells Sponges miR-204–5p, which targets Runt-related transcription factor 2 (Runx2) to promote osteoblast differentiation in aortic valve calcification (83)
TTTY15 Human cardiomyocyte primary cells Sponges miR-455–5p, which targets Jun dimerization protein 2 (JDP2) to attenuate hypoxia-induced cardiomyocytes injury (84)
X-inactive specific transcript (XIST) Cardiomyocytes (H9c2 cells) Sponges miR-101 to enhance the expression of Toll-like receptor 2 (TLR2) (85)
X-inactive specific transcript (XIST) Neonatal mouse cardiomyocytes Sponges miR-330–3p, which targets S100 calcium-binding protein B (S100B) to modulate the progression of cardiomyocyte hypertrophy (86)
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Besides functioning as miRNA sponges?

So, what are the functions of lncRNAs besides miRNA sponges? The mechanisms of action for lncRNAs can be further divided into two major categories: 1) transcription modulation; and 2) translation modulation. The transcription modulation by a lncRNA is a transcriptional regulation through recruitment of epigenetic or transcriptional factors. Several lncRNAs have been shown to function in this capacity within the heart in recent years, including: 1) cardiac autophagy inhibitory factor (CAIF), which directly binds to p53 protein and blocks p53-mediated myocardin transcription (31); 2) cardiomyocyte proliferation regulator (CPR) directly interacts and recruits DNA (cytosine-5)-methyltransferase 3A (DNMT3A) to methylate the promoter of minichromosome maintenance 3 (Mcm3) gene, an initiator of DNA replication and cell cycle progression. This signaling cascade suppresses cardiomyocyte proliferation (32); 3) colorectal neoplasia differentially expressed (Crnde), which directly binds to SMAD family member 3 (Smad3) to block its binding to Smad-binding element (SBE) (33); 4) MANTIS, which directly binds to the chromatin modifying enzyme BRG1 (also known as ATP-dependent chromatin remodeler SMARCA4] (34); 5) nuclear paraspeckle assembly transcript 1 (NEAT1) sequesters WD-40 repeat protein 5 (WDR5), a core subunit of the human MLL and SET1 (hCOMPASS) histone H3 Lys4 (H3K4) methyltransferase complexes, from smooth muscle-specific gene loci to downregulate smooth muscle specific gene expression (35); and 6) long non-coding antisense transcript of GATA6 (GATA6-AS), which directly binds lysyl oxidase homolog 2 (LOXL2) to impair its function as tri-methylation of lysine 4 on histone H3 (H3K4me3) deaminase to control endothelial cell function (36);. Besides lncRNA itself acting as scaffold for these regulatory proteins, the lncRNA locus itself can control the expression of nearby genes, as in the case of Handsdown (Hdn), which suppresses its nearby gene Hand2, independent of Hdn RNA, by directly interacting with the 5’ region of Hand2 and its enhancer regions. (37).

Another major category of lncRNA mechanisms is translation modulation. This is the mechanism in which lncRNA affects the expression and/or function of proteins by binding directly to them. When such a mechanism is restricted to the recent findings in the heart, the following lncRNAs can be highlighted: 1) antisense Igf2r RNA (Airn), which directly binds to insulin-like growth factor 2 mRNA-binding protein 2 (Igf2bp2) to control the translation of mRNAs via Igf2bp2 (38); 2) cardiac conduction regulatory RNA (CCRR), which directly binds to Cx43-interacting protein of 85 kDa (CIP85) to block endocytic trafficking of connexin43 (Cx43) (39); 3) endogenous cardiac regeneration-associated regulator (ECRAR), which directly binds to extracellular signal-regulated kinases 1 and 2 (ERK1/2) to promote their phosphorylation, leading to the activation of the downstream targets, cyclin D1 and cyclin E1 as well as E2F transcription factor 1 (E2F1) (40); (40)4) long noncoding RNA of DACH1 (LncDACH1), which directly binds to sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) and enhances its ubiquitination, leading to the reduction of SERCA2a protein to impair calcium handling and cardiac function (41); (48)and 5) ZNFX1 antisense RNA 1 (ZFAS1), which directly binds to sarco/endo plasmic reticulum calcium (Ca2+) ATPase cardiac isoform (SERCA2a) protein to limit its intracellular level and inhibit its activity (42). Because translation modulation is based on the binding of proteins to lncRNA, lncRNAs can be viewed as sidekick to the functions elicited by the binding proteins. An alternative view to this rather pessimistic view about lncRNAs is that lncRNAs fine-tune the functions of proteins by assisting (or directing) their subcellular localization and/or mode of actions, which ultimately influence cardiac structures and functions as in the case of LncDACH1 and ZFAS1.

Conclusion

In the last decade, we have witnessed a shift in our understanding of lncRNAs, which were once considered transcriptional products of junk DNA. It is now hard to argue that lncRNAs are not simply transcriptional noise but in fact important functional RNA species that influence a host of cellular processes. In the cardiovascular research field, a surge of in vitro studies have helped to improve our understanding of lncRNAs in cardiomyocyte biology; however, in vivo studies using knockout and transgenic mice remain scarce (32, 35, 37, 41, 43, 44). Thus, more genetic studies are needed to firmly establish the mechanism of action of lncRNAs in the heart.

Key points.

  • Many lncRNAs are expressed in the heart and can be easily detected by analyzing RNA-seq.

  • Increasing evidence suggests that many lncRNAs can bind miRNAs and possibly sequester them to inhibit their binding to the 3’-UTR of protein-coding genes.

  • Although in vitro experiments can elucidate the functions of lncRNAs and their mechanisms, more in vivo studies using knockout and transgenic mice are needed to understand the impact of lncRNAs to pathophysiology of the heart.

Acknowledgements:

This study was supported in part by National Institutes of Health Grant R01-HL141081 (to J.B.M.), P30-GM127607 and R01-HL149302 (to S.U.), V.V. Cooke Foundation (Kentucky, U.S.A.; to S.U.), and the startup funding from the Mansbach Family, the Gheens Foundation, and other generous supporters at the University of Louisville (to S.U.). Conflict of interest: none.

Disclosures: Both authors have been supported by the National Institute of Health and other funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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